Patients with an autonomic neuropathy frequently have severe constipation unresponsive to our current therapeutic armementarium. We recently demonstrated that i.v. neostigmine increases colonic contractility and transit in healthy volunteers; neostigmine also increased colonic tone and improved symptoms in one patient with autonomic neuropathy and intractable constipation. Pyridostigmine is an acetylcholinesterase inhibitor with higher bioavailability than neostigmine. Hypotheses - 1. In patients with slow transit constipation due to an autonomic neuropathy resulting from diabetes, pure autonomic failure, an immune-mediated process or multiple system atrophy, the acetylcholinesterase inhibitor pyridostigmine is safe, well tolerated, will improve colonic transit and satisfaction with bowel habits. 2. The effect of intravenous neostigmine on colonic tone during a motility study will predict treatment success with pyridostigmine. Aims - To assess the safety, tolerability, effect on symptoms, colonic transit and satisfaction with bowel movements of pyridostigmine in patients with constipation due to an autonomic neuropathy, and to determine if neostigmine's effects on the colonic pressure-volume relationship during a motility study predict the therapeutic response to pyridostigmine. Methods - Open-label, phase II pilot study of an escalating dose of pyridostigmine (60 mg t.i.d. to 180 mg t.i.d) in 10 patients with an autonomic neuropathy and constipation. A two-week run-in single-blind placebo phase will be followed by a 6-week single-blind treatment phase. Standard clinical assessments and a radionuclide whole-gut transit study will be performed at the beginning and end of the study. The effect of i.v. neostigmine on colonic tone and compliance will be assessed prior to the therapeutic trial. Primary endpoints are the effect of pyridostigmine on colonic transit and patient reported satisfaction with bowel movements during the last 2 weeks of the treatment period. Secondary endpoints are derived from the Rome Criteria for constipation (number of stools/week, stool consistency, frequency of straining and incomplete evacuation) and the proximal colonic emptying rate. A total of 10 patients in this pilot study should provide sufficient information to estimate the response magnitude and variability of the quantitative primary response variable, colonic transit. Significance - A successful therapeutic response in >6/10 patients in this pilot study will lead to an placebo-controlled study of pyridostigmine in a similar patient population and perhaps other patient groups with constipation due to an autonomic neuropathy.